Adipocyte-conditioned medium induces resistance of breast cancer cells to lapatinib
| Autor: | Lars Petter Jordheim, M. Lachat, Eva-Laure Matera, L. Molina, L. Conilh, Minh Ngoc Duong, Kamel Chettab, S. Beaumel, Aline Geneste, Charles Dumontet, Aurore Cleret |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Resistance
Adipose tissue Antineoplastic Agents Breast Neoplasms Mice SCID Lapatinib 030226 pharmacology & pharmacy Cell Line 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Breast cancer lcsh:RA1190-1270 Adipocytes HER2 Adipocyte medicine Animals Humans Lipolysis Pharmacology (medical) skin and connective tissue diseases Protein Kinase Inhibitors lcsh:Toxicology. Poisons Pharmacology Chemistry Cell Cycle lcsh:RM1-950 In vitro lcsh:Therapeutics. Pharmacology Drug Resistance Neoplasm SKBR3 Cell culture Culture Media Conditioned Cancer cell Cancer research Female Research Article medicine.drug |
| Zdroj: | BMC Pharmacology and Toxicology, Vol 21, Iss 1, Pp 1-12 (2020) BMC pharmacology & toxicology, vol. 21, no. 1, pp. 61 BMC Pharmacology & Toxicology |
| ISSN: | 2050-6511 |
| DOI: | 10.1186/s40360-020-00436-z |
| Popis: | Background The existence of a cross-talk between peritumoral adipocytes and cancer cells has been increasingly investigated. Several studies have shown that these adipocytes protect tumor cells from the effect of anticancer agents. Methods To investigate a potential protective effect of adipocyte-conditioned medium on HER2 positive breast cancer cells exposed to tyrosine kinase inhibitors (TKI) such as lapatinib, we analyzed the sensitivity of HER2 positive breast cancer models in vitro and in vivo on SCID mice in the presence or absence of adipocytes or adipocyte-conditioned medium. Results Conditioned medium from differentiated adipocytes reduced the in vitro sensitivity of the HER2+ cell lines BT474 and SKBR3 to TKI. Particularly, conditioned medium abrogated P27 induction in tumor cells by lapatinib but this was observed only when conditioned medium was present during exposure to lapatinib. In addition, resistance was induced with adipocytes derived from murine NIH3T3 or human hMAD cells but not with fibroblasts or preadipocytes. In vivo studies demonstrated that the contact of the tumors with adipose tissue reduced sensitivity to lapatinib. Soluble factors involved in this resistance were found to be thermolabile. Pharmacological modulation of lipolysis in adipocytes during preparation of conditioned media showed that various lipolysis inhibitors abolished the protective effect of conditioned media on tumor cells, suggesting a role for adipocyte lipolysis in the induction of resistance of tumor cells to TKI. Conclusions Overall, our results suggest that contact of tumor cells with proximal adipose tissue induces resistance to anti HER2 small molecule inhibitors through the production of soluble thermolabile factors, and that this effect can be abrogated using lipolysis inhibitors. |
| Databáze: | OpenAIRE |
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